by Bill Shore
The real challenge was to make sure the vaccine was free of pathogens, free of bacteria and fungi, and free of salivary-gland material (from which people can have allergic reactions). For this, Steve and everyone else acknowledge the indispensable role of Steve’s wife, Kim Lee. She never spoke or presented from the podium, perhaps because her contribution represents such proprietary intellectual capital that very little could be said about it.
Hoffman was transparent about the difficulties that lay ahead for introducing the vaccine into human beings. “We still don’t know how to give it. Before it was given by the bite of an infected mosquito. We can’t do that. We don’t know the number of doses or the interval between them, and so we have to do a dose escalation study. I don’t know if this will be administered subcutaneously, or muscular, or what. There’s no way to know.” What is the best route? The best volume? The best site on the body? Steve is the first to admit that he doesn’t know.
“THE LIVER IS WHERE THE WAR WILL BE WON”
By the end of the day at Sanaria’s ribbon-cutting ceremony, the government officials had moved on to search for new limelights in which to bask and the audience had thinned somewhat, leaving mostly longtime and hard-core malaria advocates spread out among the folding chairs that stretched to the back of the room.
Superlatives continued to echo through the air. Almost everything that could be said about the path to Steve Hoffman’s vaccine development strategy and its wisdom had already been said. But the closing speaker, John McNeil, from PATH, following at least a dozen other distinguished dignitaries, gave the day its exclamation point. He quoted a memorable line from Maurice Hilleman, the creator of vaccines for mumps, measles, rubella, chickenpox, and hepatitis B, and discoverer of more than three dozen vaccines in all, who is widely believed to be the most successful vaccinologist in history.
McNeil reminisced for the audience about the time Hilleman told him, “If you want to get rid of malaria, kill it in the liver. That’s where the war will be won!” Since Hilleman died in 2005, he has become an even greater icon in global health circles. Quoting his recommendation for a vaccine that attacks the Plasmodium falciparum parasite in the liver was like quoting General Dwight D. Eisenhower on how to repel an invasion of Europe.
I thought back to the time many months before when Hoffman had leaned over the large illustration of the parasite’s life cycle. Vaccinologists often fall back on military terminology. They use the language of invasion and resistance, attack and defend, kill and protect. One reason may be that many of the men and women working in tropical medicine had little choice but to enlist in the military, which used to have the best, if not the only, research labs. Their discipline, precision, and language was shaped in that crucible. They respect the parasite as an elusive and deadly adversary, one that has historically been able to withstand everything they threw at it and come back stronger.
But the effort to eradicate malaria resembles war in many ways that go beyond the language of metaphor. First and foremost, it is truly a battle to the death. The victors will survive and the losers will perish. The effort continues until, like war, the opponent is vanquished. But it is a war being fought not against the backdrop of a visible political agenda, whether extremist, ethnic, or imperialist, but instead in the nearly invisible vortex of evolution’s long and seemingly infinite forces. If the Cold War was, in the words of President John F. Kennedy, “a long twilight struggle,” the war against malaria is one of the longest of all evolutionary battles. It has entailed deception, reconnaissance, aggression, stealth, and lethal weapons.
Allied medical experts in every corner of the globe find themselves both competing and collaborating to identify the malaria parasite’s point of greatest vulnerability. Thus, in Zambia, at the Malaria Institute of Macha, 80 miles from Lusaka, the staff of the Johns Hopkins School of Public Health study why some kids get severe malaria and some do not.
In Uganda, Sweden’s Karolinski Institute and Makerere University study how the malaria parasite conceals itself in the placenta of pregnant women, causing women with their first pregnancy to lose the immunity usually found in African adults.
Tony Holder at the National Institute for Medical Research in London targets the blood stage to see what must be done to lock out merozoites from red blood cells. David Kaslow at NIH is working on a vaccine that mosquitoes would suck up in human blood. It would stop the parasite from reproducing within the mosquito and put an end to mosquitoes being able to transmit the parasite.
The Centre for Novel Agricultural Products at the University of York is using $13.6 million from the Gates Foundation to fast-track a breeding program for the sweet wormwood plant (Artemisinin annua) to create nongenetically modified varieties that will increase yields.
In 2010, the United Nations Children’s Fund, UNICEF, will distribute 25 million insecticide-treated bed nets to protect children from being bitten at night by malaria-infected mosquitoes.
In research funded by the Wellcome Trust and the National Institutes of Health, a study led by Dr. Nick Beare of the St. Paul’s Eye Unit in Liverpool has shown that changes to the retina were the only clinical sign or laboratory test that could distinguish between patients who actually died from cerebral malaria and those with another cause of death. These changes are visible with just an ophthalmoscope, making it possible to track the disease in Africa, where there’s a shortage of expensive medical equipment.7
Malaria cases soared in the KwaZulu Natal province of South Africa after it stopped using DDT in 1996, and the reintroduction of DDT in 2000 brought the disease back under control. That is enough for other countries, such as Uganda and Kenya, to examine whether DDT could also work for them. The Ugandan minister of health, Jim Muhwezi, recently defended the plan to use DDT for indoor spraying in his country, emphasizing the need for a proactive rather than reactive strategy against malaria.
Researchers at the Johns Hopkins Malaria Research Institute, whose malaria control strategy is premised on replacing malaria-carrying mosquitoes with malaria-resistant mosquitoes, determined that genetically modified mosquitoes, known as “transgenic,” fared better than their natural counterparts when fed malaria-infected blood. Such mosquitoes block transmission of the deadly parasite. The success of their theory depends on transgenic mosquitoes producing more offspring and having lower mortality than natural wild mosquitoes.
These are only a handful of the efforts underway at universities, schools of medicine and public health, field clinics, military labs, pharmaceuticals, nonprofits, and global health organizations. As in war, there are soldiers and there are generals, and among the generals a few of the most daring become known throughout their field and then beyond it.
The ongoing size of the struggle was confirmed by the final speaker at Hoffman’s ribbon-cutting event. Dr. Adel Mahmoud, president of Merck Vaccines from 1999 to 2005, who now teaches at Princeton University’s Woodrow Wilson School of Public and International Affairs, offered a sober note of warning: “A vaccine in the next year or two? Come on, folks, let’s be real. It’s going to take a lot longer than that. Eradication? It’s a nice goal, but we have eradicated only one disease in all of history, and that of course is smallpox. In not one vaccine today do we understand the mechanism of protection. Not one.”
The bet laid down in Rockville is that, long odds notwithstanding, man’s creative genius—at least one man’s—will win out in the end. In a way, it is as if Steve Hoffman has borrowed a lesson from one of Barcelona’s most celebrated creative geniuses—not his friend and competitor Pedro Alonso, but the late Antonio Gaudi. The fabled, iconic architect built his models from nature, capturing the geometry of structure and adopting essential principles from the lines, shapes, fibers, and textures he observed. Believing that natural structures had millions of years of perfect functioning to their credit, Gaudi often mimicked them in his work. From seashells to beehives, from mushrooms to ears of corn, the ingenuity of nature, for Gaudi, offered clues to effective func
tion. He once said that nature was “the Great Book, always open, that we should force ourselves to read.”8
Steve Hoffman has done no less. Sanaria’s live, attenuated sporozoite vaccine comes directly from nature’s book, and by meticulously recreating the immunity that is triggered upon the accumulation of 1,000 mosquito bites, it may mirror nature in its purest form.
After three decades of experimenting with recombinant DNA technology, which is engineered through the combination of one or more DNA strands that would not normally occur together, Hoffman is pioneering a return to first principles, and especially to the kind of natural solutions Gaudi sought out.
Paradoxically, nature’s purity is so complex that recreating its essence requires an engineering technology of mind-boggling sophistication. That’s what Sanaria has invented. Using biomolecular jujitsu, Hoffman has managed to turn the parasite’s strengths against itself. As if adopting Gaudi’s famous phrase that “originality is returning to the origin,” Hoffman returned to the origins of the Nussenzweigs’ work of an earlier generation. If it works, it will be the salvation of generations to come. The applause heard within the space of just a few days—from Seattle for Melinda Gates to Maryland for Steve Hoffman—was the sound of history accelerating.
CHAPTER 9
ECOSYSTEM OF MARKET FAILURES
What could the sex lives of algae have to do with finding a vaccine for malaria and other parasitic diseases? Quite a lot, it seems, because pond algae and the mosquito-borne Plasmodium parasite that causes malaria turn out to use the same protein to fuse their male and female gametes during sexual reproduction.
William Snell at the University of Texas Southwestern Medical Center in Dallas and colleagues discovered that . . . when [the protein] HAP2 was knocked out in Plasmodium, mosquitoes failed to spread malaria between mice. . . .
A vaccine designed to block HAP2 could break Plasmodium’s reproductive cycle in people infected with malaria and so prevent its transmission to others.
—“Algal Sex Could Spawn Malaria Vaccine,” New Scientist, April 20, 2008
OF THE WIDE VARIETY OF approaches being tried to eradicate malaria, some are mainstream, many not, but almost all fall into one of three categories: vaccination of those who have not had malaria, medication for those who do have it, or prevention through bed nets, spraying, and the like.
One reason there are so many approaches is that the problem has been so intractable. Another reason is that there is no natural market for the solutions that would serve to control them. Markets not only deliver capital and resources, they do so in ways that are efficient. Foundations, which are insulated from market forces, do not. Most nonprofits were established in response to a market failure. Whether providing health care to new immigrants, food to the hungry, or teachers and principals to inner-city schools, nonprofits fill gaps left by either the marketplace or the government because economic or political incentives to fill them were lacking. The typical fate of many good ideas in the nonprofit sector is initial popular support that fuels short-term growth, followed by gradual, long-term growth stymied by lack of sustainable resources.
But changes are afoot in the nonprofit world, and it is no longer business (or philanthropy) as usual. Advocates for the use of market mechanisms to accomplish social objectives have grown in number and now include Bill Gates. In a 2007 Harvard commencement address that called for “a more creative capitalism,” Gates proposed that we “stretch the reach of market forces so that more people can make a profit, or at least make a living, serving people who are suffering from the worst inequities.”1
Gates did not explain what he meant by “stretch the reach of market forces.” He never mentioned “social entrepreneurship.” But some of the Gates Foundation grants and grant partners are illustrative of the concept and can give us a glimpse of a future for nonprofits that harnesses market forces and thereby allows them to achieve more than ever before.
A prime example is the foundation’s investment in GAVI (formerly known as the Global Alliance for Vaccines and Immunization), which develops vaccines for HIV, malaria, and tuberculosis and improves access to these vaccines for children in poor countries. Gates and GAVI helped to create a new financing mechanism by which foundations and industrialized nations promise to subsidize the future purchase of a vaccine not yet available (up to a predetermined price). Called Advance Market Commitment, the mechanism is designed to encourage potential suppliers to invest in the R&D and production capacity needed to develop and manufacture the vaccines. They will be more likely to make that investment, in other words, if they know there will be a viable market for the end product. It is philanthropic spending intentionally designed to leverage commercial investment.
Gates’s strategy with GAVI recognizes that the qualities that make for visionary and intrepid scientists are anathema to marketeers. Great scientists are willing to face down hundreds of years of failure in pursuit of the ultimate game-changing success, whereas marketeers, able to perceive the appetites and enthusiasms of the general public today, are less interested in the ill-defined appetites and enthusiasms of an unknown future. Scientists capable of making breakthrough discoveries are often idealists; marketeers are usually pragmatists. The scientists behind breakthrough discoveries are visionaries; marketeers look at the bottom line. Gates realized that he needed to support, even create, a market mechanism for the visionaries, whose general detachment from the mass market made them indifferent, if not ignorant, to many practical considerations.
New Yorker writer James Surowiecki described the impact and the rationale for such an approach:A couple of weeks ago, Gordon Brown, Britain’s Chancellor of the Exchequer, made a promise. The United Kingdom, he said, would buy up to three hundred million doses of a new malaria vaccine for the developing world. . . . It was . . . a dramatic innovation in the way those diseases are fought. . . .
What Brown’s announcement guarantees is that if an effective vaccine emerges there will be someone to buy it at a fair price.
Usually, a company that invents something useful doesn’t have much trouble selling it. But vaccines—especially for diseases in the developing world—are notorious exceptions to this rule. To begin with, Third World countries have unimaginably tiny amounts to spend on public health. (The poorer African countries spend eighteen dollars per person a year on health. We spend five thousand dollars.) And then the market value of a vaccine may be a fraction of its social value. If you’re vaccinated, it not only makes you safer; it makes me and my children safer, too.2
What Gates and others are nurturing is a new kind of nonprofit that strategically repositions itself and directs its energies toward long-term market solutions. By this logic, an NGO, or nongovernmental organization, becomes an MDO, or “market-directed organization.” Hoffman has positioned Sanaria as just such an enterprise. Even though it is a for-profit biotech company, it has been capitalized by philanthropic dollars. Its future investment is dependent not only on effective clinical trial results but on the kind of profitable market, made up of military personnel, tourists, and business travelers, that Hoffman estimates to be worth billions of dollars.
Some nonprofits are taking a less extreme path. To supplement their fundraising, they are leveraging their assets and creating profitable revenue streams through the sale of goods and services, engaging in cause-related marketing partnerships. A market-directed organization goes beyond that trend, taking steps that make it more conducive for markets to act responsively toward it. They are developing metrics to assess return on investment and instill accountability, for example, and ensuring greater transparency about impact. They are also pursuing financing strategies that include the use of debt and equity and paying attention to long-term capacity building to create built-to-last organizations.
For even the most well-intentioned NGOs, none of this comes naturally. But a variety of strategies has already emerged from the new breed of nonprofits remaking themselves as MDOs. In addition to the efforts describ
ed above, these include: • Fee-for-service: College Summit helps talented low-income students navigate the college access process. Valuable to school districts that compete for the best ratios of college-going graduates, this national nonprofit organization created a new model for nonprofits: Philanthropy covers its national overhead costs, but fees paid by schools cover local costs as the organization expands into new communities to provide services. This market mechanism enables College Summit to grow without spiraling dependence on charitable gifts.
• Creation of community wealth: More organizations are leveraging their assets to generate earned revenues. In Baltimore, the Caroline Center, which provides job training for women, runs a furniture-reupholstering business. In Rockville, Maryland, the Jewish Social Services Agency runs a private-duty home-health-care service. Each generates new revenues to support its nonprofit mission.
• Public/private partnerships: The Reinvestment Fund, The Food Trust, and the Greater Philadelphia Urban Affairs Coalition created the Pennsylvania Fresh Food Financing Initiative to increase the number of supermarkets offering fresh and nutritious foods to underserved communities whose needs would not be met through conventional financing institutions A $30 million appropriation from the state legislature was combined with private resources from The Reinvestment Fund to establish a grant and loan program that has provided funding for eighty-three supermarkets in thirty-four Pennsylvania counties. It is an excellent example of political, nonprofit, and market forces combining to serve a public need.
• Investment in entrepreneurs: The Acumen Fund is a nonprofit that invests philanthropic dollars in business enterprises that deliver affordable and critical goods and services in poor countries. Investments include Kashf, a commercially viable financial services company making small loans to women in Pakistan, and the A to Z Textile Mill in Tanzania, a privately owned company employing 2,000 people that produces insecticide-treated bed nets to prevent malaria. An initial investment of $375,000 by Acumen enabled A to Z to scale up production and lower its costs per net. It is now the largest bed-net manufacturer in Africa.
